This invention relates to a method for lowering intraocular pressure, treating ocular hypertension, and treating glaucoma, by administering indole analogues and pharmaceutical compositions.
Glaucoma is a slowly progressive blinding disease usually associated with chronic elevation of intraocular pressure (IOP). Sufficiently high and persistent intraocular pressure is believed to result in damage to the optic disc at the juncture of the optic nerve and retina, resulting in degeneration of retinal ganglion cells and blindness characteristic of glaucoma. However, the mechanism whereby IOP elevation (also known as ocular hypertension) leads to glaucoma is not well understood. Additionally, a fraction of patients with typical visual field loss associated with glaucoma do not show abnormal elevated IOP levels (known as low-tension or normal-tension glaucoma).
Glaucoma is primarily classified as open-angle, closed-angle, or congenital, and further classified as primary and secondary. Glaucoma is treated with a variety of pharmacological and surgical approaches. In cases where glaucoma is associated with ocular hypertension, pharmacological treatment comprises adrenergic agonists (epinephrine, dipevefrin, apraclonidine), cholinergic agonists (pilocarpine), beta blockers (betaxolol, levobunolol, timolol), carbonic anhydrase inhibitors (acetazolamide) or more recently, prostaglandin analogues (latanoprost, bimatoprost (Lumigan(trademark))) and alpha adrenergic agonists (brimonidine). These pharmacological approaches help restore the IOP to a normotensive state either by inhibiting the production of aqueous humor by the ciliary body, or facilitating trabecular or uveoscleral aqueous humor outflow. Anticholinergic agents reduce intraocular pressure in primary glaucoma, reducing the resistance to outflow of the aqueous humor outflow. Anticholinesterase inhibitors have been used to manage primary and certain forms of secondary glaucoma, such as aphakic glaucoma following cataract extraction. The congenital form of glaucoma rarely responds to therapy and is more commonly treated with surgery. In narrow angle glaucoma, the aqueous outflow is enhanced by freeing of the entrance to the trabecular space at the canal of Schlemm from blockade by the iris, as a result of the drug-induced contraction of the sphincter muscle of the iris. (Taylor, pp. 123-125, in The Pharmacological Basis of Therapeutics, 7th Ed, Eds., A. G. Gilman, L. S. Goodman, T. W. Rail, and F. Murad, MacMillan Publishing Company, New York, (1985)).
In wide-angle, or chronic simple glaucoma, the entry to the trabeculae is not physically obstructed; the trabeculae, a meshwork of pores of small diameter, lose their patency. Contraction of the sphincter muscle of the iris and the ciliary muscle enhances tone and alignment of the trabecular network to improve resorption and outflow of aqueous humor through the network to the canal of Schlemm (Watson, Br. J. Opthalmol. 56: 145-318 (1972); Schwartz, N. Engl. J. Med., 290: 182-186 (1978); Kaufman, et al., Handbook of Experimental Pharmacology 69: 149-192 (1984)).
Acute congestive (narrow angle) glaucoma is nearly always a medical emergency in which the drugs are essential in controlling the acute attacks, but long-range management is usually based predominantly on surgery (peripheral or complete iridectomy). By contrast, chronic simple (wide-angle) glaucoma has a gradual, insidious onset and is not generally amenable to surgical improvement; and control of intraocular pressure depends upon permanent therapy.
Acute congestive glaucoma may be precipitated by the injudicious use of a mydriatic agent in patients over 40 years, or by a variety of factors that can cause pupillary dilatation or engorgement of intraocular vessels. Signs and symptoms include marked ocular inflammation, a semidilated pupil, severe pain, and nausea. The therapeutic objective is to reduce the intraocular pressure to the normal level for the duration of the attack. An anticholinesterase agent is instilled into the conjunctival sac in combination with a parasympathomimetic agent for greatest effectiveness. A commonly used combination consists of a solution of physostigmine and salicylate, 0.5%, plus pilocarpine nitrate, 4%. Adjunctive therapy includes the intravenous administration of a carbonic anhydrase inhibitor such as acetozolamide to reduce the secretion of aqueous humor, or of an osmotic agent such as mannitol or glycerin to induce intraocular dehydration. The long-acting organophosphorus compounds are not indicated in narrow-angle glaucoma because of vascular engorgement and increase in the angle block.
Therapy of chronic simple glaucoma and secondary glaucoma includes: (1) parasympathomimetic agents (e.g. pilocarpine nitrate, 0.5 to 0.6%); (2) anticholinesterase agents that are short-acting (e.g. physostigmine salicylate, 0.25 and 0.5%) or long-acting (demecarium bromide, 0.125 to 0.25%; echothiophate iodide, 0.03 to 0.25%; isoflurophate, 0.025%); (3) beta-adrenergic antagonists such as timolol maleate, a long-acting agent that is administered at 12-hour intervals, does not directly affect pupillary aperture, but reduces production of aqueous humor (Boger, et al., Am. J Opthalmol. 86: 8-18 (1978); Lotti, et al., Handbook of Experimental Pharmacology 69: 249-278 (1984)) and avoids the partial block of accommodation and the untoward effects of the long-acting anticholinesterase agents; and, paradoxically, (4) sympathomimetic agents (e.g. epinephrine, 0.25 to 2%, phenylephrine, 10%), which are most effective when used in combination with anticholinesterase inhibitors or cholinergic agonists. They reduce intraocular pressure by decreasing secretion of the aqueous humor, and prevent engorgement of the small blood vessels.
Because the cholinergic agonists and cholinesterase inhibitors block accommodation, they induce transient blurring of far vision, usually after administration of relatively high doses over shorter duration. With long-term administration of the cholinergic agonists and anticholinesterase agents, the response diminishes due to a diminished number of acetylcholine receptors.
Despite the convenience of less frequent administration and the high potency of long-acting anticholinesterase agents, the use of long-acting anticholinesterase agents is associated with a greater risk of developing lenticular opacities and untoward autonomic effects. An organophosphorus agent, DFP, has the longest duration of action and is extremely potent when applied locally; solutions in peanut or sesame oil require installation from once daily to once weekly, and may control intraocular pressure in severe cases that are resistant to other drugs. Because the oily vehicle is unpleasant to most patients, DFP has been replaced by echothiophate.
Treatment of glaucoma with potent, long-acting anticholinesterase agents (including demecarium, echothiophate, and isoflurophate) for 6 months or longer is associated with a high risk of developing cataracts. (Axelsson, et al., Acta Opthalmol. (Kbh.) 44: 421-429 (1966); de Roetth, J.A.M.A. 195: 664-666 (1966); Shaffer, et al., Am. J. Opthalmol. 62: 613-618 (1966)) Although development of cataracts is common in untreated comparable age groups, the incidence of lenticular opacities under such circumstances can reach 50%, with the risk increasing in proportion to the strength of the solution, frequency of installation, duration of therapy, and age of patient. (Laties, Am. J Opthalmol. 68: 848-857 (1969); Kaufman, et al., pp. 149-192, in Pharmacology of the Eye, Handbook of Experimental Pharmacology, Vol. 69, Ed. M. L. Sears, Springer-Verlag, Berlin, (1984)).
Long-acting anticholinesterase agents are not recommended when glaucoma can be controlled by timolol, parasympathomimetic drugs, physostigmine, or other agents. Nevertheless, the long-acting cholinesterase inhibitors retain their therapeutic importance in situations where other agents are inadequate, since glaucoma may lead to irreversible blindness if not adequately controlled.
Treatment with pilocarpine (4%) alone or in combination with physostigmine (0.2%) one to five times daily was found to cause no higher incidence of the development of lenticular opacities that appeared spontaneously in untreated patients in comparable age groups (Axelsson, Acta Opthalmol. (Kbh., Suppl. 102, 1-37 (1969)). Thus, pilocarpine and other short-acting miotic drugs can be used to control intraocular tension. If ineffective, the hazards of cataract development must be balanced against those of increased intraocular pressure before resorting to the use the potent, long-acting anticholinesterase agents. However, patients should be examined for the appearance of lenticular opacities at intervals of 6 months or less.
Other new agents have been assessed for treatment of glaucoma, including an A3 subtype adenosine receptor antagonist, a calmodulin antagonist, and an antiestrogen (WO 00/03741); an oligonucleotide which may be substituted, or modified in its phosphate, sugar, or base so as to decrease intraocular pressure (U.S. Pat. No. 5,545,626); a class of pyrazine, pyrimidine, and pyridazine derivatives, substituted by a non-aromatic azabicyclic ring system and optionally by up to two further substituents (U.S. Pat. No. 5,219,849); and Latanoprost, a prostacyclin analogue (Higginbotham, Arch. Opthalmol. 114: 998-999 (1996)). Four classes of compounds with promising clinical potential for the long-term management of glaucoma include topically active carbonic anhydrase inhibitors, selective alpha-2 adrenergic agonists, prostaglandins, and ethacrynic acid (Serle, Drugs Aging 5: 156-170 (1994)).
Miscellaneous ocular side effects that may occur following instillation of anticholinesterase agents are headache, brow pain, blurred vision, phacodinesis, pericorneal injection, congestive iritis, various allergic reactions and, rarely, retinal detachment. When anticholinesterase drugs are instilled intraconjunctivally at frequent intervals, sufficient absorption may occur to produce various systemic effects that result from inhibition of anticholinesterase and butyryl-cholinesterase. Hence, cholinergic autonomic function may be enhanced, the duration of action of local anesthetics with an ester linkage prolonged, and succinylcholine-induced neuromuscular blockade enhanced and prolonged. Individuals with vagotonia and allergies are at particular risk.
Latanaprost (Xalatan(copyright)) is a prostanoid agonist that is believed to reduce IOP by increasing the uveoscleral outflow of aqueous humor. Latanoprost is an isopropyl ester prodrug, and is hydrolyzed by esterases in the cornea to the biologically active acid. Xalatan(copyright) is prescribed for once-daily dosing and is shown to be equivalently effective as twice-daily dosing of 0.5% timolol. Xalatan(copyright) may gradually change eye color by increasing the amount of brown pigment in the iris. This long-term effect on the iris is unknown. Eyelid skin darkening has also been reported in associated with the use of Xalatan(copyright). In addition, Xalatan(copyright) may gradually increase the length, thickness, pigmentation, and number of eyelashes. Macular edema, including cystoid macular edema, has been reported during treatment with Xalatan(copyright). These reports have mainly occurred in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema. ((Ophthalmic PDR, 315-316 (2001).)
In summary, although a wide variety of pharmaceutical treatments for lowering IOP are available for the glaucoma patient, these treatments are limiting either in terms of efficacy or side-effects.
Melatonin is a neurohormone secreted primarily by the pineal gland and also in small amounts, by the retina. Melatonin production follows a circadian rhythm with levels increasing during the night. Melatonin is known to regulate many aspects of circadian rhythm, such as the processing of periodic information. Its mechanisms of action include the activation of melatonin membrane receptors, classified into three types, MT1 (previously known as mel1a), MT2 (previously known as mel1b or ML1) and MT3 (previously known as ML2), and anti-oxidative protection against oxidative injury through radical scavenger activity. Similar to muscarinic and purinergic receptors, MT1 and MT2 receptors belong to the superfamily of putative seven transmembrane domain G-protein coupled receptors. Both MT1 and MT2 receptors have been cloned and are negatively coupled to adenylate cyclase via a pertussis toxin-sensitive G-protein. MT3 has not been cloned and seems to be coupled to phospholipase C. (Mullins, et al.., Cell Signal 9, 169-173 (1997)) Studies have shown that MT1 receptors mediate rat caudal artery vasoconstriction and inhibition of neuronal firing associated with somnogenic effects, whereas MT2 receptors mediate rat caudal artery vasodilatation and phase advancement of circadian rhythms. (Marco, et al., Current Medicinal Chemistry 6, 501-518 (1999)). The MT3 receptor has been characterized using the high affinity ligand, 5-(methoxycarbonyl-amino)-N-acetyltryptamine (5-MCA-NAT), also known as GR 135531 (Molinari, et al., European J. Pharmacol. 301, 159-168 (1996)) although no physiological activity was reported.
The involvement of melatonin in regulating intraocular pressure (IOP) is unclear, and previous work has shown that melatonin can increase or decrease IOP, depending on the species and time during circadian rhythm that the IOP is measured. (Chiou and McLaughlin, Ophthalmic Res. 16: 302-306 (1984); Rohde, et al., J. Ocul. Pharmacol. 1: 235-243 (1985); Chiou, et al., Ophthalmic Res. 17: 373-8 (1985); Rohde, et al., Ophthalmic Res. 25: 10-15 (1993); Meyer-Bothling, et al., Invest. Ophthalmol. Vis. Sci. 34: 3035-3042 (1993); Osborne, Acta Neurobiol. Exp. (Warsz) 54 Suppl: 57-64 (1994); Aimoto, et al., J. Ocul. Pharmacol. 1: 149-160 (1985); Wilsoet, et al., Ophthalmic Physiol. Opt. 13: 357-165 (1993); Dkhissi, et al., J Neuroendocrinol. 10: 863-869 (1998); Ritch, Curr. Opin. Opthalmol. 11: 78-84 (2000); Kiuchi, et al., Curr. Eye Res. 12: 181-190 (1993); Dubocovich, et. al., FASEB J. 12, 1211-1220 (1998)). The majority of studies show that melatonin increases IOP. However, U.S. Pat. No. 4,654,361 discloses a method of lowering intraocular pressure by administering an effective amount of melatonin. This and other U.S. patents cited herein are hereby incorporated in their entirety.
U.S. Pat. No. 4,803,218 discloses a method of treating hypertension in an animal by administering a pharmaceutical composition comprising a [3-(aminoalkyl)-1H-indol-5-yl]urea compound and a pharmaceutically-acceptable carrier. This patent also teaches methods of making N-[3-(2-Aminoethyl)-1H-indol-5-yl]urea and related analogues. U.S. Pat. Nos. 5,633,276, 6,040,451, 5,948,804 and 6,159,998 disclose methods of using substituted 5-(2-imidazolin-2-ylamino)indole compounds for lowering intraocular pressure, presbyopia, treating migraine, hypertension, alcohol withdrawal, drug addiction, rheumatoid arthritis, ischemic pain, spasticity, diarrhea, nasal decongestion, and urinary incontinence. U.S. Pat. Nos. 6,004,991, 6,140,372, 59,998,461, and 6,071,946 disclose methods of treating complaints associated with melatonin disorders. Methods of syntheses of substituted indole derivatives disclosed in the above-mentioned patents are incorporated herein by reference.
PCT International Application WO 96/25397 discloses indole derivatives active at cannabinoid receptors and their use for lowering intraocular pressure and treating glaucoma. PCT International Application WO 96/11685 discloses indole derivatives for the treatment of glaucoma and other disorders. The indole derivatives disclosed in the above two PCT applications are different from those of the present invention.
As described above, agents commonly used to treat glaucoma may cause adverse side effects, such as the development of cataracts. There exists a need for agents that are both safe and effective in treating glaucoma.
Disclosed herein is a novel method of reducing intraocular pressure by administering compounds of Formulae I, II, III, and IV, which possess a core indole or melatonin-type chemical structure.
The present invention provides a method of using such compounds for reducing intraocular pressure with increased duration and/or magnitude of action compared to melatonin. A preferred compound is 5-(methoxycarbonylamino)-N-acetyltryptamine (MCA-NAT), also known as GR 135531, (Molinari, et al., Eur. J. Pharmacol. 301, 159-168 (1996)), a high affinity ligand with specificity for the MT3 receptor.
The present invention provides a method of reducing intraocular pressure and treating disorders associated with intraocular pressure such as ocular hypertension and glaucoma. The method comprises the step of administering to a subject in need thereof an indole derivative in an amount effective to reduce intraocular pressure. The indole derivatives of Formulae I, II, III, and IV, have a prolonged duration of action and/or increased efficacy in reducing intraocular pressure.